- Nella presente analisi sono stati analizzati simultaneamente i dati dei trial clinici relativi a due anticorpi monoclonali diretti contro l’IL-17A per il trattamento della psoriasi (secukinumab e ixekizumab) al fine di predire in maniera quantitativa il profilo di target engagement nella cute psoriasica.
- Mentre la quantificazione diretta dei livelli di IL-17A libera nel sito d’azione è tecnicamente complessa, gli approcci integrati di mPBPK-MBMA (minimal physiologically-based pharmacokinetic) possono offrire una stima quantitativa per facilitare lo sviluppo futuro di farmaci per la psoriasi.
Abstract
Introduction
The pharmacologic effect(s) of biotherapeutics directed against soluble targets are driven by the magnitude and duration of free target suppression at the tissue site(s) of action. Interleukin (IL)-17A is an inflammatory cytokine that plays a key role in the pathogenesis of psoriasis.
Methods
In this work, clinical trial data from two monoclonal antibodies (mAbs) targeting IL-17A for treatment of psoriasis (secukinumab and ixekizumab) were analyzed simultaneously to quantitatively predict their target engagement (TE) profiles in psoriatic skin. First, a model-based meta-analysis (MBMA) for clinical responses was conducted separately for each drug based on dose. Next, a minimal physiologically-based pharmacokinetic (mPBPK) model was built to assess skin site IL-17A target engagement for ixekizumab and secukinumab simultaneously. The mPBPK model captured the observed drug PK, serum total IL-17A, and skin drug concentration-time profiles reasonably well across the different dosage regimens investigated.
Results
The developed mPBPK model was then used to predict the average TE (i.e., free IL-17A suppression) in skin achieved over a 12-weeks treatment period for each drug following their respective regimens and subsequently assess the TE-efficacy response relationship. It was predicted that secukinumab achieved 98.6% average TE in the skin at 300 mg q4w SC while ixekizumab achieved 99.9% average TE under 160 mg (loading) followed by 80 mg q2w SC.
Conclusion
While direct quantification of free IL-17A levels at the site of action is technically challenging, integrated mPBPK-MBMA approaches offer quantitative predictions of free IL-17A levels at the site of action to facilitate future drug development via IL-17A suppression in psoriasis.